Neuropathic pain is a form of chronic pain that can persist for months, years or decades following an injury, and results from damage to peripheral nerves, nerve roots, the spinal cord or certain brain regions. It differs from nociceptive pain in terms of duration, characteristics, underlying mechanisms and treatment (Bennett G. J. (1994a) In: Textbook of Pain (Ed. Wall P D, Melzack R) Churchill Livingstone, London 3rd edn, 201). Neuropathic pain can consist of spontaneous pain (e.g., burning, cutting, tingling), evoked pain (e.g., allodynia evoked by stimulation of non-nociceptive afferents, and hyperalgesia evoked by stimulation of nociceptive afferents) and paroxysmal pain (e.g., originating from a trigger point, described as stabbing, lancinating, shocklike) (Bennett G. J. (1994a) In: Textbook of Pain (Ed. Wall P D, Melzack R) Churchill Livingstone, London 3rd edn, 201). Neuropathic pain can accompany nociceptive pain, and multiple treatment strategies may be required for optimal alleviation of pain (Portenoy R. K. (1991) In: Towards a New Pharmacology of Pain (Ed. Basbaum A I, Besson J. M.) John Wiley & Sons Ltd, New York, 393; Devor M, Basbaum A. I., Bennett ., Blumeberg H, Campbell et al (1991) In: Towards a New Pharmacotherapy of Pain (Ed. Basbaum A I, Besson J. M.) John Wiley & Sons, New York, 417). Neuropathic syndromes are traditionally classified according to the disease or event that precipitated them (e.g., postherpetic neuralgia following shingles, causalgia following partial damage to a major nerve, central pain following a thalamic infarct) (Portenoy R. K. (1991) In: Towards a New Pharmacology of Pain (Ed. Basbaum A. I., Besson J. M.) John Wiley & Sons Ltd, New York, 393; Merskey H, Bogaduk N (1994) In: Classification of Chronic Pain. Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms, 2nd edn, IASP Press, Seattle, page 40). The involvement of the sympathetic nervous system in a number of these conditions has been appreciated for some time. Pain syndromes with a sympathetic component are considered as sympathetically maintained pain (reflect sympathetic dystrophy, causalgia) (Bonica J. J. (1990) In: The Management of Pain (Ed. Bonica J. J.) Lea & Fibiger, Philadelphia 2nd edn. Bonica (1990, 220; Blumeberg H., Janig W. (1994) In: Textbook of Pain (Ed. Wall P D, Melzack R) Churchill Livingstone, London 3rd edn, 685).
Neuropathic pain is particularly difficult to treat clinically. The use of opioids is controversial, with issues of contention being the relative refractoriness of neuropathic pain compared to nociceptive pain, the need for higher doses with an increased incidence of side effects to achieve partial effects, and concerns over the long term use of opioids in a non-malignant context (Arner S, Meyerson B A (1988) Pain 22: 11; Kuypers H., Konig H., Adriaenson H., Gybels J. M. (1991) Pain 47: 5; Portenoy R. K., Foley K. M., Inturrisi C. E. (1990) Pain 43: 273; Portenoy R. K. (1994) In: Progress in Pain Research and Management (Ed. Fields H. L., Liebskind J. C.) IASP Press, Seattle, 247). The major classes of agents currently used to treat neuropathic pain include systemically delivered antidepressants, anticonvulsants, local anesthetics, and specialized agents such as muscle relaxants, and sympatholytic drugs (reviewed Portenoy R. K. (1991) In: Towards a New Pharmacology of Pain (Ed. Basbaum A I, Besson J. M.) John Wiley & Sons Ltd, New York, 393; Portenoy R. K. (1993) Drug Therapy 23: 41; Max M B (1994) In: Progress in Pain Research and Management (Ed. Fields H. L., Liebskind J. C.) IASP Press, Seattle, 229). However, many of these treatments show limited effectiveness (complete pain relief is rarely achieved), and there is a high incidence of debilitative side effects (Portenoy R. K. (1993) Drug Therapy 23: 41; Bennett G. J. (1994a) In: Textbook of Pain (Ed. Wall P D, Melzack R) Churchill Livingstone, London 3rd edn, 201; Mac Farlane et al., (1997) Pharmacol. Ther. 75:1).
Damage to nerves can activate changes in both the peripheral and central nervous systems, and these lead to the characteristic expression of neuropathic pain. Peripherally, the following mechanisms may be involved (reviewed by Devor M, Basbaum A I, Bennett G. J., Blumeberg H, Campbell et al (1991) In: Towards a New Pharmacotherapy of Pain (Ed. Basbaum A I, Besson J. M.) John Wiley & Sons, New York, 417; Devor M (1994) In: Textbook of Pain (Ed. Wall P D, Melzack R) Churchill Livingstone, London, 3rd edn, 79; Blumeberg H, Janig W (1994) In: Textbook of Pain (Ed. Wall P D, Melzack R) Churchill Livingstone, London 3rd edn, 685). (1) Following injury, normally silent nociceptors become sensitized and acquire an ongoing spontaneous activity, a lowered threshold for activation, and a heightened response to suprathreshold stimulation. (2) Development of ectopic discharges can occur at the site of injury, site of regeneration and neuroma formation, or within the dorsal root ganglion. (3) Following injury, sympathetic afferents can excite sensory nerve endings, regenerating nerve sprouts, neuromas, and the dorsal root ganglion cell. Central mechanisms implicated in neuropathic pain are as follows (Coderre et al., (1993) Pain 52:259; Bennett (1994) In: Textbook of Pain (ed. by P. D. Wall et al., London, 3rd edn., 201; Woulff and Doubell (1994) Curr. Opin. Neurobiol. 4:525): (1) Transmission neurons within the spinal cord exhibit enhanced sensitivity to excitation by excitatory amino acids (EAAs) and substance P (SP). This condition leads to allodynia (following AB fibre activation) and hyperalgesia (following A.delta. and C fibre activation). (2) Disinhibition resulting from loss of inhibitory input to projection neurons and an aberrant patterning of responses to large diameter afferent activation. (3) Myelinated afferents, which normally would enervate deeper laminae, projecting into and making synaptic connections in more superficial laminae. This can be a mechanism for the generation of allodynia.
A number of models of neuropathic pain have been developed in order to provide a basis for understanding of neuropathic changes that occur following nerve injury, and to provide model systems in which to test novel therapeutic strategies (reviewed Bennett G. J. (1994b) In: Progress in Pain Research and Management Vol 2 (Ed. Gebhart C F, Hammond D L, Jensen T S) IASP Press, Seattle, 495). The best characterized are a number of nerve injury models which have been developed only relatively recently (chronic constriction injury due to loose ligation of the sciatic nerve, Bennett G. J., Xie Y. K. (1988) Pain 33: 87; and partial sciatic ligation due to tight ligation of a portion of the sciatic nerve (Seltzer et a. (1990) Pain 43:205) and tight ligation of two spinal nerves (Kim S. H., Chung J. M. (1992) Pain 50: 355)). These model systems exhibit various manifestations of neuropathic pain (e.g., degree of expression of spontaneous pain behaviors, mechanical or thermal allodynia, mechanical or thermal hyperalgesia) and degree of sympathetic nerve involvement (Neil A, et al. (1991) Brain Res 565: 237; Shir Y., Seltzer Z. (1991) Pain 45: 309; Kim S H, Na H S, Sheen Ki, Chung J M (1993) Pain 55: 85; Kim K J, Yoon Y W, Chung J M (1997) Exp Brain Res 113: 200). The spinal nerve ligation (SNL) model exhibits a greater degree of evoked pain (mechanical allodynia) and of sympathetic involvement in this parameter than do the partial sciatic ligation or chronic constriction injury models, while the chronic constriction injury model exhibits a greater degree of spontaneous pain. It is however appreciated that such properties may be relative and change with time (i.e., sympathetic dependency can change with time both in animal models and in clinical neuropathic pain, Staton-Hicks M, Janig W, Hassenbusch S, Haddox J D, Boas R, Wilson P (1995) Pain 63: 127).
Systemically administered antidepressants offer an alternate therapy in neuropathic and chronic pain states. Interactions with biogenic amines, endogenous opioids, excitatory amino acid receptors, substance P and calcium and sodium channels have been considered in efforts to pinpoint the mechanism of systemically administered antidepressants (reviewed by Eschalier A, Mestre C, Dubray C, Ardid D (1994) CNS Drugs 2: 261). What is clear is that antidepressants can act at both supraspinal (Spiegel, K., Kalb, R. and Pasternak, G. W., Ann. Neurol. 13 (1983) 462-465, Eschalier A, Mestre C, Dubray C, Ardid D (1994) CNS Drugs 2: 261) and spinal (Hwang, A. S. and Wilcox, G. L., Pain 28 (1987) 343-355; Iwashita, T. and Shimizu, T., Brain Research 581 (1992) 59-66; J. Eisenachand G. F.Gebhart, Anesthesiology 83 (1995) 1046-1054) sites of action.
This analgesic action is independent of antidepressant effects as it occurs in non-depressed subjects and occurs independently of mood changes in depressed subjects (Magni G (1991) Drugs 42: 730; Onghena P, Van Houdenhove B (1992) Pain 49: 205; Max M B (1994) In: Progress in Pain Research and Management (Ed. Fields H L, Liebskind J C) IASP Press, Seattle, 229, McQuay H J, Tramer M, Nye B A, Carroll D, Wiffen P J, Moore R A (1996) Pain 68: 217). Agents which block the uptake of both noradrenaline (NA) and 5-hydroxytryptamine (5-HT) such as amitriptyline, or which block NA but not 5-HT, such as desipramine, are more effective than those with selectivity for 5-HT, such as fluoxetine (Max M B (1994) In: Progress in Pain Research and Management (Ed. Fields H L, Liebskind J C) IASP Press, Seattle, 229). Pain relief is reported to be apparent within one week of therapy (McQuay H J, Carroll D, Glynn C J (1992) Anaesthesia 47: 646). This time course corresponds to the time required to attain stable plasma levels (t1/2 17-36 hours in humans, Ziegler V E, Biggs J T, Aardekani A B, Rosen S H (1978) J Clin Pharmacol 18: 462). By contrast, the antidepressant activity of these compounds takes 4-6 weeks to become apparent (Potter W Z, Rudorfer M, Manji H (1991) New Eng J Med 325: 633). These differences in profile of active drugs, time course, and independent expression of effects suggest that mechanisms underlying pain relief and alleviation of depression differ.
In animal tests, both the systemic and spinal administration of antidepressants show intrinsic efficacy in a number of nociceptive pain tests, and augment analgesia produced by opioids (reviewed by Eschalier A, Mestre C, Dubray C, Ardid D (1994) CNS Drugs 2: 261). However, this profile can be variable, and inhibitory effects on the action of morphine have been observed in some cases (reviewed by Eschalier et al., supra). Methodological issues (e.g., test paradigm, intensity of stimulus, dose, regimen of acute versus chronic administration) are reported to account for many of these differences (Kellstein D E, Malseed R T, Goldstein F J (1984) Pain 60: 275; Kellstein D E, Malseed R T, Ossipov M H, Goldstein F J (1988) Neuropharmacology 27: 1; Fialip J, MartyH, Makambila M C, CiViate M A, Eschalier A (1989) J Pharmacol Exp Ther 248: 747). Systemically administered antidepressants also exhibit intrinsic actions in a number of neuropathic pain tests including nerve transaction (Seltzer Z, Tal M, Sherav Y (1989) Pain 37: 245), mononeuropathy (Ardid D, Gilbaud G (1992) Pain 49: 279) and diabetic neuropathy models (C.Courteix et al.(1994) Pain 57:153-160). One study examined chronic versus acute dosing regimens (Ardid D, Gilbaud G (1992) Pain 49: 279), and observed that the activity seen following chronic paradigms appeared to be accounted for by accumulating doses rather than being qualitatively different.